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Rheumatoid arthritis (RA) patients got no benefit from vagus nerve stimulation (VNS) in a , in sharp contrast to previous open-label studies, researchers said.

Only 25.0% of 52 patients receiving active unilateral stimulation achieved so-called ACR20 responses (20% improvement in symptoms by American College of Rheumatology criteria) after 12 weeks of treatment, compared with 26.9% of 52 control patients given an inactive device, according to Matthew C. Baker, MD, MS, of Stanford University in California, and colleagues.

More clinically meaningful responses were even rarer, the team : ACR50 and ACR70 responses (50% and 70% improvement, respectively) were seen in 13.5% and 5.8%, respectively, of the active-treatment group, versus 7.7% and 3.8% among sham-treated patients.

Bilateral stimulation given to nine patients was somewhat more effective, with 44.4% of the active-treatment group having ACR20 responses. Still, only 11.1% achieved ACR50 responses; the same number met ACR70 criteria.

Standard drug therapies typically yield ACR20 response rates in the range of 50%-70%; ACR70 rates upwards of 20% are common.

The new results were somewhat surprising insofar as a number of earlier (but smaller and less rigorous) studies were substantially more favorable. Underlying the approach is earlier research indicating that immune activity is influenced by a nervous-system phenomenon known as the "inflammatory reflex." As Baker and colleagues explained it, "[v]agus nerve afferents sense molecular products of infection and injury, and efferents stimulate immune cells in the spleen in a regulatory fashion, ultimately blocking production of inflammatory cytokines," such as tumor necrosis factor and interleukin-6.

"It is hypothesized that this reduction in systemic inflammation can be harnessed for the treatment of diseases such as RA," the researchers continued, by artificially stimulating the vagus nerve. Both the new trial and an earlier one tested a wearable earbud-type device by a California company called Nēsos that delivers electrical stimulation to the nerve's auricular branch serving the ear.

, by a group that included Baker and other investigators in the new trial, showed ACR20/50/70 responses in line with drug trials. But that study was small and had no control group.

An , by prominent RA trialist Roy Fleischmann, MD, of the University of Texas Southwestern Medical Center in Dallas, pointed out that these were problems with other previous clinical studies of VNS. Even some of those, he wrote, showed only "minimal" improvements in disease activity, and only a small proportion of patients achieved remission or low disease activity -- the primary goal in RA treatment.

"[A]n open-label, single-arm study design without proper powering and an invasive procedure is more likely to show positive results than a properly powered, large, double-blind sham-controlled trial," which the new one was, Fleischmann observed.

Study Details

Baker and colleagues enrolled a total of 113 patients with active, moderately severe RA despite treatment with conventional drugs such as methotrexate. As is typical in RA, most were women, mean age was 54, with disease duration of about 7 years.

Patients continued on their previous regimens and were told to use the earbud devices, applied to the external ear, for 15 minutes once each day for 12 weeks. Bilateral application was instituted after the first six patients were randomized, but then terminated shortly afterward on the advice of outside consultants in order to concentrate on unilateral stimulation's effects.

Adverse effects were few and mostly related to the patients' RA. Ear discomfort, reported by four patients, was the only adverse effect clearly related to the device.

Fleischmann highlighted a common problem with all medical trials involving electrical stimulation devices -- the nearly infinite potential combinations of electrical intensity and frequency, dosing schedule, and duration of treatment. "It has yet to be determined whether stimulation more than once daily (BID or TID), perhaps with less or equal intensity, will provide superior efficacy to what has been published," he wrote.

In addition, he commented, patient selection might also have been suboptimal, and perhaps the efficacy could have been improved if stimulation was combined with newer targeted RA drugs.

He stopped short of calling VNS a dead end in RA, however. "[T]here are currently ongoing well-designed, prospective, large, sham-controlled trials with different VNS devices inserted at different locations," he noted.

"Hopefully," he added, these trials "will answer the question as to whether there is a role for VNS in the treatment of RA."